PROJECT SUMMARY/ABSTRACT Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. This project's long-term goal is to develop more effective clinical therapy through the discovery and improved understanding of glaucoma pathogenesis. We want to learn how to modify underlying disease mechanisms to an extent that it significantly alters the natural course of disease, preserves vision, and positively impacts patients' lives. This is particularly important in dealing with a chronic, unrelenting disease such as POAG. POAG is of unknown cause, although clinical features and risk factors are known: intraocular pressure (IOP), increasing age, corneal thickness and retinal ganglion cell loss. Levels of transforming growth factor-2 (TGF?2) in the aqueous humor are elevated and can be considered an important disease biomarker. This can affect the trabecular meshwork's function of regulating physiological aqueous outflow and IOP by inducing fibrogenic change and excessive contractility. Resulting rising IOP damages the retinal ganglion cells, optic nerve and vision. Current IOP-lowering glaucoma therapy targets physiological mechanisms of IOP regulation rather than underlying pathological mechanisms responsible for causing IOP to rise in the first place. We cannot therapeutically target these pathological mechanisms mainly because we do not know what the primary problem is. We have discovered that a mouse with a fibrillin-1 genetic mutation uncannily mimics salient clinical and biochemical features of human POAG. The genetic defect of the mouse immediately invokes pathogenic mechanisms related to fibrillin-1. It offers a unique opportunity to better understand and treat this mysterious and important disease. We propose the following specific aims to: (1) characterize the source of elevated aqueous TGF?2; (2) assess routes of TGF?2 activation in the eye tissues and aqueous humor; and (3) test a strategy to prevent harmful effects of aqueous TGF?2 on the trabecular meshwork and IOP that damages retinal ganglion cells. The mouse model will allow us to better understand the basis for aqueous TGF?2 elevation in POAG and test a treatment strategy to ameliorate development and progression of the disease.